Is MPL p.Ser179Pro (c.535T>C) pathogenic?

MPL p.Ser179Pro (c.535T>C) is classified Uncertain significance in MPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely benign (0.1039); Ultra-rare (popmax 0.0117%, nfe); Associated with congenital amegakaryocytic thrombocytopenia.

What condition is associated with MPL p.Ser179Pro (c.535T>C)?

MPL p.Ser179Pro (c.535T>C) is associated with congenital amegakaryocytic thrombocytopenia, essential thrombocythemia (ClinVar).

How common is MPL p.Ser179Pro (c.535T>C) in the general population?

MPL p.Ser179Pro (c.535T>C) is ultra-rare (popmax 0.0117%, nfe) (gnomAD).

What do computational predictors say about MPL p.Ser179Pro (c.535T>C)?

AlphaMissense predicts likely benign (score 0.1039) — an in-silico prediction, not a clinical call.

MPL p.Ser179Pro

c.535T>C · rs746331868 · VCV2150915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1039 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital amegakaryocytic thrombocytopenia

Computational evidence

Protein change
AlphaMissense	0.1039	likely benign
REVEL	0.527	indeterminate
SaProt	LLR -8.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.15	GERP -3.3, phastCons 0.011
Regional constraint	o/e 0.80	unconstrained · MANE · 8,947 bp · p 8.9e-06 · regional, not allelic
Overall
CADD	8.774	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% European (non-Finnish) · 138/1,180,022 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00948%

Overall 0.00892% 144/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0117%	8,551
Admixed American	0.005%	19,997
Remaining individualsnot grpmax-eligible	0.0048%	20,829

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MPL
Protein: p.Ser179Pro
Coding: c.535T>C
MANE Select: NM_005373
dbSNP: rs746331868
Type: single nucleotide variant
Location: chr1:43339414 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.44 · 1 PDB
Residue 179: the fibronectin type-iii 1 domain

Full MPL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital amegakaryocytic thrombocytopenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: essential thrombocythemia

Similar variants

MPL p.Ser179Tyr Uncertain significance ★ ⚠ same residue
MPL c.1165+1G>C Likely pathogenic ★★ same condition
MPL c.1166-1G>C Likely pathogenic ★★ same condition
MPL c.1468+2T>C Pathogenic/Likely pathogenic ★★ same condition
MPL c.1469-2A>T Pathogenic/Likely pathogenic ★★ same condition
MPL c.1566-1G>A Likely pathogenic ★★ same condition
MPL c.1653+1G>C Likely pathogenic ★★ same condition
MPL c.79+2T>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mpl-p-ser179pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown